Dopamine Receptors in Breast Cancer: Prevalence, Signaling, and Therapeutic Applications.

Breast cancer (BC) is the most common malignancy among women, with over one million cases occurring annually worldwide. Although therapies against estrogen receptors and HER2 have improved response rate and survival, patients with advanced disease, who are resistant to anti-hormonal therapy and/or to chemotherapy, have limited treatment options for reducing morbidity and mortality. These limitations provide major incentives for developing new, effective, and personalized therapeutic interventions. This review presents evidence on the involvement of dopamine (DA) and its type 1 receptors (D1R) in BC. DA is produced in multiple peripheral organs and is present in the systemic circulation in significant amounts. D1R is overexpressed in ~ 30% of BC cases and is associated with advanced disease and shortened patient survival. Activation of D1R, which signals via the cGMP/PKG pathway, results in apoptosis, inhibition of cell invasion, and increased chemosensitivity in multiple BC cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in mouse models with D1R-expressing BC xenografts. It is proposed that D1R should serve as a novel diagnostic/prognostic factor through the use of currently available D1R detection methods. Fenoldopam, which is FDA-approved to treat renal hypertension, could be repurposed as an effective therapeutic agent for patients with D1R-expressing tumors. Several drugs that interfere with the cGMP/PKG pathway and are approved for treating other diseases should also be considered as potential treatments for BC.

Pharmacologic Control of Blood Pressure in Infants and Children.

Alterations in blood pressure are common during the perioperative period in infants and children. Perioperative hypertension may be the result of renal failure, volume overload, or activation of the sympathetic nervous system. Concerns regarding end-organ effects or postoperative bleeding may mandate regulation of blood pressure. During the perioperative period, various pharmacologic agents have been used for blood pressure control including sodium nitroprusside, nitroglycerin, ß-adrenergic antagonists, fenoldopam, and calcium channel antagonists. The following manuscript outlines the commonly used pharmacologic agents for perioperative BP including dosing regimens and adverse effect profiles. Previously published clinical trials are discussed and efficacy in the perioperative period reviewed.

Fenoldopam Mesylate: A Narrative Review of Its Use in Acute Kidney Injury.

BACKGROUND: Fenoldopam mesylate is a selective agonist of DA-1 receptors. It is currently used for the in-hospital treatment of severe hypertension. DA-1 receptors have high density in renal parenchyma and for this reason, a possible reno-protective role of Fenoldopam mesylate was investigated. METHODS: We examined all studies regarding the role of Fenoldopam mesylate in Acute Kidney Injury (AKI); particularly, those involving post-surgical patients, intensive care unit patients and contrastinduced nephropathy. RESULTS: Fenoldopam mesylate was found to be effective in reducing the onset of postoperative AKI, when used before the development of the kidney damage. Positive results were also obtained in the management of intensive care unit patients with AKI, although the clinical studies investigated were few and conducted on small samples. CONCLUSION: Conflicting results were achieved in contrast-induced nephropathy.

Does Fenoldopam Protect Kidney in Cardiac Surgery? A Systemic Review and Meta-Analysis With Trial Sequential Analysis.

PURPOSE: To assess the benefits and harms of fenoldopam for nephroprotective effects in adult patients undergoing cardiac surgery. METHODS: We conducted a systematic review with meta-analysis of randomized controlled trials (RCTs) comparing fenoldopam with placebo in cardiac surgery. Trials were systematically searched from PubMed, EMBASE, CENTRAL, and CNKI databases, up to July 30, 2018. A trial sequential analysis (TSA) was used to determine whether the present evidence was valid and conclusive for the primary outcomes. RESULTS: A total of seven randomized controlled trials involving 1,107 adult patients undergoing cardiac surgery fulfilled the inclusion criteria. The pooled analysis suggested that the use of fenoldopam was associated with a reduction in the incidence of AKI (18 of 216 [8.3%] in the fenoldopam group versus 45 of 222 [20.3%] in the placebo group, RR = 0.42 [0.26, 0.69], P = 0.0006) and with a higher rate of hypotension (92/357 [25.8%] versus 51/348 [14.7%], RR = 1.76 [1.29, 2.39], P = 0.0003). There was no significant effect on renal replacement therapy requirement (77 of 540 [14.3%] versus 75 of 536 [14.0%], P = 0.96) or hospital mortality (87/392 [22.2%] versus 83/383 [21.7%], P = 0.86). TSA supported the results of the conventional analysis on AKI. CONCLUSIONS: Low-dose dopamine offers transient improvements in renal physiology, but no good evidence shows that it offers important clinical benefits to patients with or at risk for acute renal failure.Among patients treated with fenoldopam, there was a decrease in AKI and an increased incidence of hypotension, had no significant effect on RRT or mortality. Given that most studies were small and the definition of AKI was variable between studies, there is not enough evidence to support the systematic use of fenoldopam in cardiac surgery.

Personalized Nanotherapy by Specifically Targeting Cell Organelles To Improve Vascular Hypertension.

Ciliopathies caused by abnormal function of primary cilia include expanding spectrum of kidney, liver, and cardiovascular disorders. There is currently no treatment available for patients with cilia dysfunction. Therefore, we generated and compared two different (metal and polymer) cilia-targeted nanoparticle drug delivery systems (CTNDDS), CT-DAu-NPs and CT-PLGA-NPs, for the first time. These CTNDDS loaded with fenoldopam were further compared to fenoldopam-alone. Live-imaging of single-cell-single-cilium analysis confirmed that CTNDDS specifically targeted to primary cilia. While CTNDDS did not show any advantages over fenoldopam-alone in cultured cells in vitro, CTNDDS delivered fenoldopam more superior than fenoldopam-alone by eliminating the side effect of reflex tachycardia in murine models. Although slow infusion was required for fenoldopam-alone in mice, bolus injection was possible for CTNDDS. Though there were no significant therapeutic differences between CT-DAu-NPs and CT-PLGA-NPs, CT-PLGA-NPs tended to correct ciliopathy parameters closer to normal physiological levels, indicating CT-PLGA-NPs were better cargos than CT-DAu-NPs. Both CTNDDS showed no systemic adverse effect. In summary, our studies provided scientific evidence that existing pharmacological agent could be personalized with advanced nanomaterials to treat ciliopathy by targeting cilia without the need of generating new drugs.

Effects of fenoldopam on kidney function parameters and its therapeutic efficacy in the management of acute kidney injury in dogs with heatstroke.

BACKGROUND: Acute kidney injury (AKI) is common in dogs, but evidence of efficacy of its treatment is lacking. OBJECTIVE: To evaluate the efficacy of fenoldopam in the management of AKI. ANIMALS: Forty dogs with naturally occurring heatstroke. METHODS: Dogs were prospectively enrolled and divided into treatment and the placebo groups (fenoldopam, constant rate infusion [CRI] of 0.1 µg/kg/min or saline, respectively). Urine production (UP) was measured using a closed system. Urinary clearances were performed at 4, 12, and 24 hours after presentation to estimate the effect of fenoldopam on UP, glomerular filtration rate (GFR) and sodium fractional excretion (NaFE). RESULTS: At presentation, severity of heatstroke, based on a previously developed scoring system, was similar between the study groups, but was significantly worse in nonsurvivors compared with survivors. Fenoldopam administration was not associated with hypotension. Overt AKI was diagnosed, based on the International Renal Interest Society guidelines in 22/40 (55%) of the dogs. Overall, 14/40 dogs (35%) died, with no significant (P = .507) mortality rate difference between the fenoldopam (6/20 dogs; 30%) and placebo (8/20; 40%) groups. The proportion of dogs with AKI did not differ between the fenoldopam and the placebo groups (9/20; 45% versus 13/20; 65%, respectively; P = .204). There were no differences in UP, GFR, and NaFE between the fenoldopam and the placebo groups. CONCLUSION AND CLINICAL IMPORTANCE: Fenoldopam CRI at 0.1 µg/kg/min did not have a clinically relevant effect on kidney function parameters in dogs with severe heatstroke-associated AKI.

Prevention of acute kidney injury in Intensive Care Units.

Acute kidney injury (AKI) is a growing concern in Intensive Care Units. The advanced age of our patients, with the increase in associated morbidity and the complexity of the treatments provided favor the development of AKI. Since no effective treatment for AKI is available, all efforts are aimed at prevention and early detection of the disorder in order to establish secondary preventive measures to impede AKI progression. In critical patients, the most frequent causes are sepsis and situations that result in renal hypoperfusion; preventive measures are therefore directed at securing hydration and correct hemodynamics through fluid perfusion and the use of inotropic or vasoactive drugs, according to the underlying disease condition. Apart from these circumstances, a number of situations could lead to AKI, related to the administration of nephrotoxic drugs, intra-tubular deposits, the administration of iodinated contrast media, liver failure and major surgery (mainly heart surgery). In these cases, in addition to hydration, there are other specific preventive measures adapted to each condition.

Acute kidney injury following cardiac surgery: current understanding and future directions.

Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 % of patients, injures and impairs the function of the brain, lungs, and gut, and places patients at a 5-fold increased risk of death during hospitalization. Renal ischemia, reperfusion, inflammation, hemolysis, oxidative stress, cholesterol emboli, and toxins contribute to the development and progression of AKI. Preventive strategies are limited, but current evidence supports maintenance of renal perfusion and intravascular volume while avoiding venous congestion, administration of balanced salt as opposed to high-chloride intravenous fluids, and the avoidance or limitation of cardiopulmonary bypass exposure. AKI that requires renal replacement therapy occurs in 2-5 % of patients following cardiac surgery and is associated with 50 % mortality. For those who recover from renal replacement therapy or even mild AKI, progression to chronic kidney disease in the ensuing months and years is more likely than for those who do not develop AKI. Cardiac surgery continues to be a popular clinical model to evaluate novel therapeutics, off-label use of existing medications, and nonpharmacologic treatments for AKI, since cardiac surgery is fairly common, typically elective, provides a relatively standardized insult, and patients remain hospitalized and monitored following surgery. More efficient and time-sensitive methods to diagnose AKI are imperative to reduce this negative outcome. The discovery and validation of renal damage biomarkers should in time supplant creatinine-based criteria for the clinical diagnosis of AKI.

Fenoldopam to prevent acute kidney injury after major surgery-a systematic review and meta-analysis.

BACKGROUND: Acute kidney injury (AKI) after surgery is associated with increased mortality and healthcare costs. Fenoldopam is a selective dopamine-1 receptor agonist with renoprotective properties. We conducted a systematic review and meta-analysis of randomised controlled trials comparing fenoldopam with placebo to prevent AKI after major surgery. METHODS: We searched EMBASE, PubMed, meta-Register of randomised controlled trials and Cochrane CENTRAL databases for trials comparing fenoldopam with placebo in patients undergoing major surgery. The primary outcome was incidence of new AKI. Secondary outcomes were requirement for renal replacement therapy and hospital mortality. RESULTS: Eighty-three publications were screened; 23 studies underwent full data extraction and scoring. Six trials were suitable for inclusion in the data synthesis (total of 507 subjects undergoing cardiovascular surgery, partial nephrectomy, liver transplant surgery). Five studies were rated at high risk of bias. Data on post-operative incidence of AKI were available in five of the six trials (total of 471 patients) but definitions of AKI varied between studies. Of the 238 patients receiving fenoldopam, 45 (18.9%) developed AKI compared to 62 (26.6%) of the 233 patients who received placebo (p = 0.004, I (2) = 0 %; random-effects model odds ratio 0.46, 95% confidence interval 0.27-0.79). In patients treated with fenoldopam, there was no difference in renal replacement therapy (n = 478; p = 0.11, I (2) = 47%; fixed-effect model odds ratio 0.27, 95% confidence interval 0.06-1.19) or hospital mortality (p = 0.60, I (2) = 0 %; fixed-effect model odds ratio 1.0, 95% confidence interval 0.14-7.37). CONCLUSIONS: In this analysis, peri-operative treatment with fenoldopam was associated with a significant reduction in post-operative AKI but it had no impact on renal replacement therapy or hospital mortality. Equipoise remains for further large trials in this area since the studies were conducted in three types of surgery, the majority of studies were rated at high risk of bias and the criteria for AKI varied between trials.

Administration of fenoldopam in critically ill small animal patients with acute kidney injury: 28 dogs and 34 cats (2008-2012).

OBJECTIVE: To describe the clinical features and outcomes of critically ill dogs and cats with acute kidney injury (AKI) receiving fenoldopam infusions compared to patients with AKI that did not receive fenoldopam. DESIGN: Retrospective clinical study from May 1, 2008 until June 1, 2012. SETTING: Private emergency and specialty referral hospital. ANIMALS: Client-owned dogs (28) and cats (34) with AKI that received fenoldopam compared with similar patients with AKI (30 dogs and 30 cats) that did not. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The medical records of 62 critically ill dogs and cats with AKI that received fenoldopam were reviewed. Presenting clinical signs, physical examination findings, and primary and secondary disease processes were identified in all patients. The mean number of days on fenoldopam was 1.5 days (range 0.3-4.0 days) for dogs and 1.9 days (range 1.0-4.0 days) for cats. Eleven of 28 (39%) dogs survived to discharge and 13 of 34 (38%) of the cats survived to discharge. Of the animals in the group receiving fenoldopam that died, the majority (84%) were euthanized. Potential adverse reactions were evaluated, with hypotension being the most commonly encountered adverse effect (7% of fenoldopam group [FG] dogs and 23% of FG cats). When compared with patients with AKI that did not receive fenoldopam, no significant differences were found between the groups with regards to survival, length of hospital stay, adverse effects, or changes in creatinine, BUN, or sodium concentrations except that patients receiving fenoldopam were significantly more likely to have received other renally active medications. CONCLUSIONS: In this study of patients with AKI, fenoldopam administration at 0.8 µg/kg/min in dogs and 0.5 µg/kg/min in cats appeared relatively safe but was not associated with improvement in survival to discharge, length of hospital stay, or improvement in renal biochemical parameters when compared to patients with AKI not receiving fenoldopam.

Fenoldopam for the prevention of contrast-induced nephropathy (CIN)-do we need more trials? A meta-analysis.

We conducted a pooled analysis of clinical trials comparing intravenous Fenoldopam (FP) with Saline/Placebo/N-acetyl cysteine (NAC) for the prevention of contrast-induced nephropathy (CIN). Five studies were eligible. Quantitative analyses were done with Review Manager (RevMan version 5.2.). A total of 85 out of 353 patients in Fenoldopam group while 73 among 366 in the control group were affected due to CIN. The risk ratio for the development of CIN in the Fenoldopam group was 1.19 compared to the control group. This was not statistically significant. Fenoldopam is no better than Placebo/Saline or NAC in preventing CIN, but more studies are required.

Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial.

IMPORTANCE: No effective pharmaceutical agents have yet been identified to treat acute kidney injury after cardiac surgery. OBJECTIVE: To determine whether fenoldopam reduces the need for renal replacement therapy in critically ill cardiac surgery patients with acute kidney injury. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study from March 2008 to April 2013 in 19 cardiovascular intensive care units in Italy. We randomly assigned 667 patients admitted to intensive care units after cardiac surgery with early acute kidney injury (≥50% increase of serum creatinine level from baseline or oliguria for ≥6 hours) to receive fenoldopam (338 patients) or placebo (329 patients). We used a computer-generated permuted block randomization sequence for treatment allocation. All patients completed their follow-up 30 days after surgery, and data were analyzed according to the intention-to-treat principle. INTERVENTIONS: Continuous infusion of fenoldopam or placebo for up to 4 days with a starting dose of 0.1 µg/kg/min (range, 0.025-0.3 µg/kg/min). MAIN OUTCOMES AND MEASURES: The primary end point was the rate of renal replacement therapy. Secondary end points included mortality (intensive care unit and 30-day mortality) and the rate of hypotension during study drug infusion. RESULTS: The study was stopped for futility as recommended by the safety committee after a planned interim analysis. Sixty-nine of 338 patients (20%) allocated to the fenoldopam group and 60 of 329 patients (18%) allocated to the placebo group received renal replacement therapy (P = .47). Mortality at 30 days was 78 of 338 (23%) in the fenoldopam group and 74 of 329 (22%) in the placebo group (P = .86). Hypotension occurred in 85 (26%) patients in the fenoldopam group and in 49 (15%) patients in the placebo group (P = .001). CONCLUSIONS AND RELEVANCE: Among patients with acute kidney injury after cardiac surgery, fenoldopam infusion, compared with placebo, did not reduce the need for renal replacement therapy or risk of 30-day mortality but was associated with an increased rate of hypotension. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00621790.

Therapeutic strategies to prevent contrast-induced acute kidney injury.

PURPOSE OF REVIEW: Contrast-induced acute kidney injury (CI-AKI) accounts for approximately 10% of all causes of hospital-acquired renal failure, causes a prolonged in-hospital stay, and represents a powerful predictor of poor early and late outcome. Here, we highlight endpoints used to assess major strategies to prevent CI-AKI. RECENT FINDINGS: A general consensus exists on the beneficial prophylactic effect of hydration. This seems to act by increasing urine flow rate and, thereby, by limiting the time of contact between the contrast media and the epithelial tubular cells. On the contrary, both observational trials and randomized studies are often controversial in their conclusions on the efficacy of several drugs tested to prevent CI-AKI. Compounds evaluated include diuretics (furosemide), antioxidants (i.e., N-acetylcysteine and statins), and vasodilators (i.e., calcium antagonists, dopamine, and fenoldopam). Due to the negative and/or controversial clinical results, none of these drugs has been currently recommended to prevent CI-AKI. CONCLUSION: More reliable markers of acute kidney injury and new prophylactic strategies are warranted to prevent the incidence of CI-AKI.

Fenoldopam and renal function after partial nephrectomy in a solitary kidney: a randomized, blinded trial.

OBJECTIVE: To test the hypothesis that fenoldopam administration ameliorates ischemic injury, preserving the glomerular filtration rate and serum creatinine postoperatively after partial nephrectomy in patients with a solitary kidney. MATERIALS AND METHODS: Fenoldopam is a short-acting dopamine-1 receptor agonist that might provide renal protection during ischemic stress. A total of 90 patients with a solitary functioning kidney who were undergoing partial nephrectomy were randomized to fenoldopam or placebo in a double-blind protocol. The patients assigned to fenoldopam received an infusion rate of 0.1 µg/kg/min for 24 hours. The effect of fenoldopam on renal function was assessed by comparing the groups on the change in glomerular filtration rate from baseline to the third postoperative day (primary outcome) and on the change in serum creatinine over time (secondary outcome). RESULTS: Of the 90 enrolled patients, 77 provided analyzable data (43 in fenoldopam and 44 in placebo group). Fenoldopam (vs placebo) did not reduce the mean percentage of change in the glomerular filtration rate from baseline to the third postoperative day (P = .15), with an estimated ratio of means of 0.89 (95% confidence interval 0.69-1.09) for fenoldopam vs placebo. The postoperative serum creatinine in the 2 groups changed at comparable rates from postoperative day 1 to 4 (group-by-time interaction, P = .72) after adjusting for baseline creatinine, with no difference in the mean serum creatinine over time (P = .78). CONCLUSION: Fenoldopam administration did not preserve renal function in the clinical setting of renal ischemia during solitary partial nephrectomy, as evidenced by changes in the glomerular filtration rate or serum creatinine.

Contrast-induced nephropathy: protective role of fenoldopam.

1. Contrast-induced nephropathy (CIN) often occurs after contrast media-related procedures and is associated with increased morbidity and mortality. The acute renal failure observed after administration of contrast media is usually transient but, in some cases, it can be severe enough to lead to permanent renal damage with life-long dialysis. 2. Except for saline hydration, no other treatment has been shown to have a consistent benefit in protecting against CIN. Despite sound physiological and pharmacological bases, intravenous infusion of fenoldopam does not prevent CIN. 3. Initial studies have shown the safety of and favourable results with direct infusion of fenoldopam into the renal arteries using the Benephit renal infusion system (FlowMedica-AngioDynamics, Latham, NY, USA). These results are encouraging and suggest that intrarenal delivery of fenoldopam has an advantage in patients with a high risk of developing CIN. 4. A randomized controlled study comparing intrarenal fenoldopam with placebo is warranted.